An individual's genetic makeup remains a major predisposing factor to obesity, with recent trends in diet and behavior also contributing to the current obesity epidemic. Genetic background is responsible for about half of the variation in body weight within human populations, but we currently understand only a few of the pathways affected by hereditary risk factors. Importantly, the limited information we have about obesity-predisposing genes suggests that many are expressed primarily in the brain. Indeed, the central nervous system clearly plays important but poorly understood roles in maintaining organismal energy homeostasis. Experiments in this proposal will target neuronal roles in body fat regulation in the fruit fly Drosophila melanogaster. Drosophila is a powerful obesity model: flies have a complex physiology rivaling that of mammals, plus a streamlined genome in which a single gene often serves the function of multiple redundant mammalian genes. The goals of this project are to generate a neuronal map of body fat regulation by identifying regions of the brain whose functions are required to prevent excess body fat, and to determine the functions of two genes that were identified in an unbiased screen for fat mutants and which appear to operate in the brain. One of the new fat genes is an uncharacterized receptor related to those that bind adiponectin, a mammalian protein secreted from fat cells that controls food consumption and fat storage. Identifying the molecule bound by the fly receptor may reveal a new pathway by which the brain communicates with other tissues to prevent obesity. The other gene has been implicated in both learning-related behaviors like addiction and, most importantly, the regulation of locomotor activity in response to nutrient availability. Thus, this factor may represent an otherwise elusive opportunity to dissect the relationship between physical activity and energy storage. These studies will provide new insights into the neuronal components of human obesity, and identify new potential targets for its treatment.